Submissions for variant NM_001042492.3(NF1):c.654+1G>T

dbSNP: rs1060500245

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464166	SCV000541968	pathogenic	Neurofibromatosis, type 1	2020-01-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of neurofibromatosis type-1 (NF1) and/or NF1-Noonan syndrome (PMID: 21354044, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 6 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV002356635	SCV001187569	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-10-10	criteria provided, single submitter	clinical testing	The c.654+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 6 of the NF1 gene. This mutation has been identified in an individual meeting diagnostic criteria for neurofibromatosis type 1 (NF1); authors performed RNA studies, which reportedly showed that this variant causes exon 6 skipping and a resultant truncated protein (Valero MC et al. J Mol Diagn 2011 Mar;13(2):113-22). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition to the published literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
3billion	RCV000464166	SCV002318597	pathogenic	Neurofibromatosis, type 1	2022-03-22	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000404420). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000464166	SCV002561592	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463843	SCV004199027	pathogenic	Juvenile myelomonocytic leukemia	2021-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV004721365	SCV005327256	pathogenic	not provided	2024-03-18	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21354044)